THSG alleviates cerebral ischemia/reperfusion injury via the GluN2B-CaMKII-ERK1/2 pathway.

BACKGROUND: The potential therapeutic targeting of PINK1-PARK2-mediated mitophagy against cerebral ischemia/reperfusion (CI/R) injury involves the pathophysiological processes of neurovascular unit (NVU) and is closely associated with N-methyl-D-aspartate receptors (NMDARs) commonly expressed in NVU. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-ß-D-glucoside (THSG), a compound derived from the traditional Chinese medicine Polygonum multiflorum Thunb., has demonstrated notable neuroprotective properties against CI/R injury. However, it remains unclear whether THSG exerts its protective effects through GluN2B related PINK1/ PARK2 pathway. PURPOSE: This study aims to explore the pharmacological effects of THSG on alleviating CI/R injury via the GluN2B-CaMKII-ERK1/2 pathway. METHODS: THSG neuroprotection against CI/R injury was studied in transient middle cerebral artery occlusion/reversion (tMCAO/R) model rats and in oxygen and glucose deprivation/ reoxygenation (OGD/R) induced neurons. PINK1-PARK2-mediated mitophagy involvement in the protective effect of THSG was investigated in tMCAO/R rats and OGD/R-induced neurons via THSG and 3-methyladenine (3-MA) treatment. Furthermore, the beneficial role of GluN2B in reperfusion and its contribution to the THSG effect via CaMKII-ERK1/2 and PINK1-PARK2-mediated mitophagy was explored using the GluN2B-selective antagonist Ro 25-6981 both in vivo and in vitro. Finally, the interaction between THSG and GluN2B was evaluated using molecular docking. RESULTS: THSG significantly reduced infarct volume, neurological deficits, penumbral neuron structure, and functional damage, upregulated the inhibitory apoptotic marker Bcl-2, and suppressed the increase of pro-apoptotic proteins including cleaved caspase-3 and Bax in tMCAO/R rats. THSG (1 µM) markedly improved the neuronal survival under OGD/R conditions. Furthermore, THSG promoted PINK1 and PARK2 expression and increased mitophagosome numbers and LC3-II-LC3-I ratio both in vivo and in vitro. The effects of THSG were considerably abrogated by the mitophagy inhibitor 3-MA in OGD/R-induced neurons. Inhibiting GluN2B profoundly decreased mitophagosome numbers and OGD/R-induced neuronal viability. Specifically, inhibiting GluN2B abolished the protection of THSG against CI/R injury and reversed the upregulation of PINK1-PARK2-mediated mitophagy by THSG. Inhibiting GluN2B eliminated THSG upregulation of ERK1/2 and CaMKII phosphorylation. The molecular docking analysis results demonstrated that THSG bound to GluN2B (binding energy: -5.2 ± 0.11 kcal/mol). CONCLUSIONS: This study validates the premise that THSG alleviates CI/R injury by promoting GluN2B expression, activating CaMKII and ERK1/2, and subsequently enhancing PINK1-PARK2-mediated mitophagy. This work enlightens the potential of THSG as a promising candidate for novel therapeutic strategies for treating ischemic stroke.

Protective effects of Zishen Huoxue recipe against neuronal injury in the neurovascular unit of rats with vascular dementia by interfering with inflammatory cascade-induced pyroptosis.

OBJECTIVE: Chinese herbal formulas show considerable therapeutic benefits in dementia. This study specifically explored the protective action of Zishen Huoxue recipe on the neurovascular unit (NVU) of rats with vascular dementia (VD). METHODS: VD rat models were established by permanent bilateral common carotid artery occlusion and treated with Zishen Huoxue recipe. In vitro glucose­oxygen deprivation (OGD)-injured NVU models were established and treated with miR-124-3p agomir or rat medicated serum. The neurological damage, histopathological changes, and neuronal injury in the rat hippocampus were assessed using Morris water maze test and histological stainings. Expression of miR-124-3p was determined using RT-qPCR. The blood-brain barrier/NVU injury, cell pyroptosis, NLRP3 inflammasome activation, and release of inflammatory factors were analyzed mainly by immunofluorescence analysis, TUNEL staining, Western blot, and ELISA. QS-21 (an NLRP3 activator) was used to verify the role of miR-124-3p/NLRP3. RESULTS: Zishen Huoxue recipe ameliorated the learning/memory deficits, neuronal injury, NVU insults, cell pyroptosis, activation of NLRP3 inflammasome, and extensive secretion of lactate dehydrogenase/IL-1ß/IL-18 in VD rats. miR-124-3p was downregulated in VD rats but upregulated after treatment of this recipe. miR-124-3p overexpression ameliorated NVU insults, reduced cell pyroptosis, lowered NLRP3 inflammasome activation, and suppressed inflammatory responses in OGD-injured NVU models. NLRP3 inflammasome activation partly counteracted the amelioration effect of miR-124-3p on pyroptosis. Zishen Huoxue recipe could upregulate miR-124-3p to suppress pyroptosis and protect NVU function. CONCLUSION: Zishen Huoxue recipe can upregulate miR-124-3p expression to repress the inflammatory cascade-evoked pyroptosis, thereby protecting against neuronal injury in the NVU of VD rats.

Beneficial effects and safety of traditional Chinese medicine for chronic inflammatory demyelinating polyradiculoneuropathy: A case report and literature review.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated neuropathy. First-line treatments for CIDP include corticosteroids, intravenous immunoglobulin, and plasma exchange. However, the application is always limited by high costs, effectiveness, and adverse events. This study investigated a new potentially effective and safe therapeutic treatment to alleviate CIDP symptoms and improve the quality of life. In the present case, a 47-year-old rural woman presented with weakness and numbness of progressive extremities. She was diagnosed with CIDP based on abnormal cerebrospinal fluid and electromyography. The patient was treated with intravenous dexamethasone for 1 week and with Huangqi-Guizhi-Wuwu and Bu-Yang-Huan-Wu decoctions for 90 days. Surprisingly, after the treatment, the weakness and numbness were eliminated, and the quality of life improved. The varying INCAT, MRC, and BI scores also reflected the treatment effects. After 8 months of discharge, the symptoms did not relapse during the follow-up. We also searched "traditional Chinese medicine (TCM)" and "CIDP" in PubMed, EMBASE, the Web of Science, the Cochrane Library, the Chinese National Knowledge Infrastructure Databases, Wanfang Data, and the Chongqing Chinese Science and Technology Periodical Database. Finally, only ten studies were included in the literature review. Three studies were randomized controlled trials, and seven were case reports or case series. There were 419 CIDP patients, but all study sites were in China. Nine TCM formulas involving 44 herbs were reported, with Huang Qi (Astragalus membranaceus) being the most important herb. In conclusion, the case and literature demonstrated that TCM treatment might be a more effective, low-cost, and safe option for treating CIDP. Although these preliminary findings are promising, a larger sample size and higher-quality randomized clinical trials are urgently required to confirm our findings.

TLR4 Enhances Cerebral Ischemia/Reperfusion Injury via Regulating NLRP3 Inflammasome and Autophagy.

Ischemic stroke is a kind of central nervous disease characterized by high morbidity, high mortality, and high disability. Inflammation and autophagy play important roles in cerebral ischemia/reperfusion (CI/R) injury. The present study characterizes the effects of TLR4 activation on inflammation and autophagy in CI/R injury. An in vivo CI/R rat injury model and an in vitro hypoxia/reoxygenation (H/R) SH-SY5Y cell model were established. Brain infarction size, neurological function, cell apoptosis, inflammatory mediators' levels, and gene expression were measured. Infarction, neurological dysfunction, and neural cell apoptosis were induced in CI/R rats or in H/R-induced cells. The expression levels of NLRP3, TLR4, LC3, TNF-α, interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-18 (IL-18) clearly increased in I/R rats or in H/R-induced cells, while TLR4 knockdown significantly suppressed NLRP3, TLR4, LC3, TNF-α, and interleukin-1/6/18 (IL-1/6/18) in H/R-induced cells, as well as cell apoptosis. These data indicate that TLR4 upregulation induced CI/R injury via stimulating NLRP3 inflammasome and autophagy. Therefore, TLR4, is a potential therapeutic target to improve management of ischemic stroke.

Meta-analysis of the relations between gut microbiota and pathogens and Parkinson's disease.

BACKGROUND: The motor symptoms in patients with Parkinson's disease (PD) are commonly preceded by gastrointestinal (GI) symptoms. The enteric nervous system (ENS) has also been reported to exhibit neuropathological characteristics of PD. OBJECTIVES: To evaluate the relationship between the incidence of parkinsonism and alteration in gut microbiota and pathogens. MATERIAL AND METHODS: Studies in different languages that evaluate the relationship between gut microorganisms and PD were included into this meta-analysis. The outcomes of these studies were analyzed using a random effects model; it was also used to calculate the mean difference (MD) with 95% confidence interval (95% CI) in order to quantify the impact of different rehabilitation techniques on clinical parameters. Dichotomous and continuous models were used for the analysis of extracted data. RESULTS: A total of 28 studies were included in our analysis. The analysis of small intestinal bacterial overgrowth showed a significant correlation with Parkinson's subjects compared with controls (p < 0.001). In addition, the presence of Helicobacter pylori (HP) infection was significantly related to the Parkinson's group (p < 0.001). On the other hand, there was a significantly higher abundance level of Bifidobacteriaceae (p = 0.008), Verrucomicrobiaceae (p < 0.001) and Christensenellaceae (p = 0.003) in Parkinson's subjects. In contrast, a significantly lower abundance levels in Parkinson's subjects were found in Faecalibacterium (p = 0.03), Lachnospiraceae (p = 0.005) and Prevotellaceae (p = 0.005). No significant difference was related to Ruminococcaceae. CONCLUSION: Parkinson's subjects showed a higher degree of alteration of gut microbiota and pathogens compared with normal human subjects. Future multicenter randomized trials are needed.

MiR-140 promotes the progression of intracranial aneurysms by targeting BCL2L2.

To investigate the role of miR-140/BCL2L2 axis on the formation of intracranial aneurysms. The expression of miR-140 in the serum of patients with intracranial aneurysms and healthy volunteers was detected. CCK-8 assay and Annexin V-FITC/PI double staining flow cytometry were used to evaluate the effect of miR-140 knockdown on the proliferation and apoptosis of human brain vascular smooth muscle cells (HBVSMCs). Meanwhile, the relationship between miR-140 and BCL2L2 was examined. MiR-140 was found to be upregulation in intracranial aneurysm patients. MiR-140 knock-out significantly inhibited the apoptosis of HBVSMCs and promoted cell proliferation. BCL2L2 was a direct target gene of miR-140 and suppressed its expression. Knockdown of miR-140 alleviates the development of intracranial aneurysms. MiR-140/BCL2L2 axis promotes the progression of intracranial aneurysms by regulating apoptosis of HBVSMCs. Therefore, miR-140 is a potential therapeutic target for intracranial aneurysms.

Association between white matter alterations and domain-specific cognitive impairment in cerebral small vessel disease: A meta-analysis of diffusion tensor imaging.

Objective: To investigate the association between diffusion tensor imaging (DTI) findings and domain-specific cognitive impairment in cerebral small vessel disease (CSVD). Methods: Databases such as PubMed, Excerpta Medical Database (EMBASE), Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure Databases (CNKI), Wanfang, Chinese Biomedical Literature Database (SinoMed), and Chongqing Chinese Science and Technology Periodical Database (VIP) were comprehensively retrieved for studies that reported correlation coefficients between cognition and DTI values. Random effects models and meta-regression were applied to account for heterogeneity among study results. Subgroup and publication bias analyses were performed using Stata software. Results: Seventy-seven studies involving 6,558 participants were included in our meta-analysis. The diagnosis classification included CSVD, white matter hyperintensities (WMH), subcortical ischemic vascular disease, cerebral microbleeding, cerebral amyloid angiopathy (CAA), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Fabry disease. The pooled estimates showed that the fractional anisotropy (FA)-overall exhibited a moderate correlation with general cognition, executive function, attention, construction, and motor performance (r = 0.451, 0.339, 0.410, and 0.319), and the mean diffusitivity/apparent diffusion coefficient (MD/ADC)-overall was moderately associated with general cognition, executive function, and memory (r = -0.388, -0.332, and -0.303, respectively; p s < 0.05). Moreover, FA in cingulate gyrus (CG), cerebral peduncle (CP), corona radiata (CR), external capsule (EC), frontal lobe (FL), fornix (FOR), internal capsule (IC), and thalamic radiation (TR) was strongly correlated with general cognition (r = 0.591, 0.584, 0.543, 0.662, 0.614, 0.543, 0.597, and 0.571), and a strong correlation was found between MD/ADC and CG (r = -0.526), normal-appearing white matter (NAWM; r = -0.546), and whole brain white matter (WBWM; r = -0.505). FA in fronto-occipital fasciculus (FOF) (r = 0.523) and FL (r = 0.509) was strongly associated with executive function. Only MD/ADC of the corpus callosum (CC) was strongly associated with memory (r = -0.730). Besides, FA in CG (r = 0.532), CC (r = 0.538), and FL (r = 0.732) was strongly related to the attention domain. Finally, we found that the sample size, etiology, magnetic resonance imaging (MRI) magnet strength, study type, and study quality contributed to interstudy heterogeneity. Conclusion: Lower FA or higher MD/ADC values were related to more severe cognitive impairment. General cognition and executive function domains attracted the greatest interest. The FL was commonly examined and strongly associated with general cognition, executive function, and attention. The CC was strongly associated with memory and attention. The CG was strongly related to general cognition and attention. The CR, IC, and TR were also strongly related to general cognition. Indeed, these results should be validated in high-quality prospective studies with larger sample sizes. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021226133.

Exploring the Mechanism of the Baishao Luoshi Formula against Poststroke Spasticity by Network Pharmacology and Experimental Validation.

BACKGROUND: Post-stroke spasticity (PSS) is a major cause of disability, leading to severely impaired upper-limb flexibility and ability to walk and move, significantly affecting the quality of life of cerebral infarction patients. There is currently no recognized effective therapy. Alternatively, Chinese traditional medicine has shown promise for PSS treatment. In this regard, the BSLSF has been reported to be effective; however, its underlying mechanism remains unclear. OBJECTIVE: The objective of this study is to clarify the main targets and pathways of Baishao Luoshi Formula (BSLSF) during PSS treatment, laying the foundation for further research on its pharmacological effects. METHODS: In this study, network pharmacology and experimental verification were conducted to explore the potential mechanism of BSLSF systematically. After obtaining active ingredients of BSLSF from the TCMSP database, SwissTarget-Prediction and PharMapper were used to uncover BSLSF targets. PSS-related targets were gathered with GeneCards and Online Mendelian Inheritance in Man. The differentially expressed genes between BSLSF and PSS were identified by a Venn plot. The drugactive ingredient-target interaction network and Protein-protein interaction (PPI) were constructed using Cytoscape and further analyzed using the MCC algorithm of CytoHubba plugin. Then, Pathway enrichment and GO biological process enrichment analyses were performed. Subsequently, a mice model of middle cerebral artery occlusion (MCAO) was established for the in vivo experiments. RESULTS: We found that AKT1, TNF, CASP3, VEGFA, and CREB1 were potential targets during PSS treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that the mechanism of PSS was closely related to synaptic plasticity. And the immunohistochemical staining showed that BSLSF protected against ischemic stroke via the CCR5/CREB signaling pathway and probably affected synaptic plasticity. CONCLUSION: our study validated that treatment with BSLSF protected against ischemic stroke via the CCR5/CREB signaling pathway and could affect synaptic plasticity. In a sense, this study provides the basis for further extensive and in-depth analysis of BSLSF, enabling the quest for new drug targets at the same time.

A randomized double-blind controlled study protocol on the efficacy and safety of Sangdantongluo granule in the treatment of post-stroke spasticity.

Introduction: Stroke is the first leading cause of mortality and disability worldwide, and post-stroke spasticity (PSS) is the common complication of stroke. Sangdantongluo Granule (Z20210481000), a modern patent Chinese medicine, is widely used in clinical practice to treat PSS. Whereas, there is limited evidence of effectiveness for Sangdantongluo Granule to treat PSS. This study will evaluate the clinical efficacy and safety of Sangdantongluo granule in the treatment of PSS. Methods: and Analysis This multicenter, randomized, double-blind and placebo-controlled study will recruit 132 participants in China who develops PSS 15 days-90 days after stroke. Participants will be randomly assigned in an equal ratio to receive either Sangdantongluo granule or placebo for 2 months twice a day orally. The primary measure is the Modified Ashworth Scale (MAS), Secondary outcome measures include Composite Spasticity Scale (CSS), Simplified Fugl-Meyer Motor Scale (S-FM), National Institute of Health stroke scale (NIHSS), Modified Rankin Scale (mRS), Modified Barther Index (MBI), and Surface electromyography. Adverse events will be supervised throughout the trial. SPSS V. 26.0 statistical software will be used for statistical analysis. Enrolment will be started in April 2022. Ethics and dissemination: The trial and protocol were approved by the Ethics Committee of Hunan Academy of Chinese Medicine Affiliated Hospital (No. [202102]20). We will report the results of this trial in a peer-reviewed journal. Trial registration: ClinicalTrials.gov ChiCTR2100044544. Registered on 23 March 2021.

SOS1-IT1 silencing alleviates MPP+-induced neuronal cell injury through regulating the miR-124-3p/PTEN/AKT/mTOR pathway.

Long non-coding RNA (lncRNA) has been found to be involved in the regulation of a variety of disease progression, including Parkinson's disease (PD). However, the role and underlying mechanism of SOS1 intronic transcript 1 (SOS1-IT1) in the progression of PD is still unclear. 1-methyl-4-phenyl pyridine (MPP+) induced SK-N-SH cells were used to construct PD cell models in vitro. The expression levels of SOS1-IT1, microRNA (miR)-124-3p and phosphatase and tensin homolog (PTEN) were determined using quantitative real-time PCR. Cell counting kit 8 assay and flow cytometry were used to measure cell viability and apoptosis. Western blot analysis was performed to detect protein expression. The levels of inflammation cytokines and oxidative stress markers were examined to assess cell inflammation and oxidative stress. In addition, dual-luciferase reporter assay, RIP assay and RNA pull-down assay were used to confirm RNA interaction. Our results showed that SOS1-IT1 was upregulated in MPP+-induced SK-N-SH cells, and its silencing reversed the inhibition effect of MPP+ on the viability and the promotion effect on the apoptosis, inflammation and oxidative stress of SK-N-SH cells. MiR-124-3p was targeted by SOS1-IT1, and its inhibitor reversed the suppressive effect of SOS1-IT1 knockdown on MPP+-induced SK-N-SH cell injury. Furthermore, PTEN was a target of miR-124-3p, and the reduction effect of miR-124-3p on MPP+-induced SK-N-SH cell injury was reversed by PTEN overexpression. Additionally, the activity of AKT/mTOR pathway was regulated by the SOS1-IT1/miR-124-3p/PTEN axis. In conclusion, SOS1-IT1 regulated the miR-124-3p/PTEN/AKT/mTOR pathway to participate in the regulation of MPP+-induced neuronal cell injury, indicating the SOS1-IT1 might be an effective therapeutic target for PD.

Efficacy and safety of naotaifang capsules for hypertensive cerebral small vessel disease: Study protocol for a multicenter, randomized, double-blind, placebo-controlled clinical trial.

Background: Hypertensive cerebral small vessel disease (HT-CSVD) is a cerebrovascular clinical, imaging and pathological syndrome caused by hypertension (HT). The condition manifests with lesions in various vessels including intracranial small/arterioles, capillaries, and small/venules. Hypertensive cerebral small vessel disease has complex and diverse clinical manifestations. For instance, it can present as an acute stroke which progresses to cause cognitive decline, affective disorder, unstable gait, dysphagia, or abnormal urination. Moreover, hypertensive cerebral small vessel disease causes 25-30% of all cases of ischemic strokes and more than 50% of all cases of single or mixed dementias. The 1-year recurrence rate of stroke in cerebral small vessel disease patients with hypertension is 14%. In the early stage of development, the symptoms of hypertensive cerebral small vessel disease are concealed and often ignored by patients and even clinicians. Patients with an advanced hypertensive cerebral small vessel disease manifest with severe physical and mental dysfunction. Therefore, this condition has a substantial economic burden on affected families and society. Naotaifang (NTF) is potentially effective in improving microcirculation and neurofunction in patients with ischemic stroke. In this regard, this multicenter randomized controlled trial (RCT) aims to furtherly evaluate the efficacy and safety of naotaifang capsules on hypertensive cerebral small vessel disease. Methods: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 388 eligible subjects were recruited from the First Hospital of Hunan University of Chinese Medicine, Hunan Academy of Chinese Medicine Affiliated Hospital, the First Hospital of Shaoyang University, the First Traditional Chinese Medicine Hospital of Changde, and Jiangmen Wuyi Hospital of Traditional Chinese Medicine from July 2020 to April 2022. After a 4-week run-in period, all participants were divided into the intervention group (represented by Y-T, N-T) and control group (represented by Y-C, N-C); using a stratified block randomized method based on the presence or absence of brain damage symptoms in hypertensive cerebral small vessel disease (represented by Y and N). The Y-T and N-T groups were administered different doses of naotaifang capsules, whereas Y-C and N-C groups received placebo treatment. These four groups received the treatments for 6 months. The primary outcome included Fazekas scores and dilated Virchow-robin spaces (dVRS) grades on magnetic resonance imaging (MRI). The secondary outcomes included the number of lacunar infarctions (LI) and cerebral microbleeds (CMB) on magnetic resonance imaging, clinical blood pressure (BP) level, traditional Chinese medicine (TCM) syndrome scores, mini-mental state examination (MMSE) scale, and safety outcomes. Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds on magnetic resonance imaging were tested before enrollment and after 6 months of treatment. The clinical blood pressure level, traditional Chinese medicine syndrome scores, mini-mental state examination scale and safety outcomes were tested before enrollment, after 3-month, 6-month treatment and 12th-month follow-up respectively. Conclusion: The protocol will comfirm whether naotaifang capsules reduce Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds, clinical blood pressure, increase mini-mental state examination scores, traditional Chinese medicine syndrome scores of Qi deficiency and blood stasis (QDBS), and improve the quality of life of subjects. The consolidated evidence from this study will shed light on the benefits of Chinese herbs for hypertensive cerebral small vessel disease, such as nourishing qi, promoting blood circulation and removing blood stasis, and dredging collaterals. However, additional clinical trials with large samples and long intervention periods will be required for in-depth research. Clinical Trial registration: www.chictr.org.cn, identifier ChiCTR1900024524.

[Situation analysis of outcome indicators of randomized controlled trials of traditional Chinese medicine in treatment of hypertensive intracerebral hemorrhage in recent three years].

The study aims to analyze the outcome indicators of randomized controlled trial(RCT) of traditional Chinese medicine(TCM) in the treatment of hypertensive intracerebral hemorrhage(HICH) in recent three years, and thus provide suggestions for the future studies in this field. Four English databases, four Chinese databases and two online registration websites of clinical trials were searched. The RCTs published between January 2018 and September 2020 were screened. The risk of bias was assessed and outcome measures were classified. A total of 151 839 articles were retrieved, of which 44 RCTs were included for analysis after screening. The outcome measures of the included RCTs were classified into 7 categories, among which the symptoms/signs category showed the highest reporting rate. National Institute of Health stroke scale(72.73%) was the most frequently reported outcome indicator, while the vo-lume of intracerebral hemorrhage determined by computerized tomography(36.36%) was the most frequently reported lab test outcome. Most studies collect the outcomes at the end of treatment, while 9 studies reported long-term outcomes 3 months or more after onset. Compared with those of international clinical trials, the application of some of the outcomes was reasonable, focusing on patients' symptoms, quality of life and objective outcomes. However, there were still several problems: unclear primary and secondary outcome measures, insufficient attention to long-term prognosis, insufficient attention to social function, few TCM outcomes, lack of measurement blindness and the use of unreasonable composite outcomes. It is recommended that researchers should rationally design the outcome indicators of clinical trials and develop the core outcome set.

Association between diffusion tensor imaging findings and domain-specific cognitive impairment in cerebral small vessel disease: a protocol for systematic review and meta-analysis.

INTRODUCTION: Cognitive impairment is the main clinical manifestation of cerebral small vessel disease (CSVD). However, the mechanism and structural damage in different domains of cognitive disorders are poorly understood. There is an urgent need to quantify the relation between diffusion tensor imaging (DTI) data and impaired cognitive testing in CSVD, which may help to find biomarkers for early diagnosis or treatment evaluation. We aim to summarise the understanding of association between DTI findings and domain-specific cognitive impairment. METHODS AND ANALYSIS: PubMed, EMBASE, Web of science, Cochrane library, Chinese National Knowledge Infrastructure Databases, Wanfang, SinoMed and VIP will be searched, from 1 January 1994 to 1 August 2021. The ClinicalTrials.gov and Chictr.org.cn records will also be searched to identify further potential studies. The included studies should report fractional anisotropy and/or and mean diffusivity/apparent diffusion coefficient data for one or more individual regions of interest in DTI analysis. Meanwhile, cognitive testing scores are also needed. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The quality of cohort or case-control studies will be evaluated by the Newcastle-Ottawa Scale, and the cross-section studies will be evaluated by Agency for Healthcare Research and Quality scale. Meta-analysis, subgroup and sensitivity analyses, and publication bias will be all performed with Stata. ETHICS AND DISSEMINATION: Patients and the public will not be involved in this study. The existing data from published studies will be used. The findings from this research will be relevant information regarding the association of DTI metrics with cognitive disorder, which will be published in a peer-reviewed journal. If we need to amend this protocol, we will give the date of each amendment, describe the change and give the rationale. Changes will not be incorporated into the protocol. PROSPERO REGISTRATION NUMBER: CRD42021226133.

Decreased spasticity of Baishaoluoshi Decoction through the BDNF/TrKB-KCC2 pathway on poststroke spasticity rats.

OBJECTIVE: K+-Cl- cotransporter-2 (KCC2), which primarily extrudes chloride in mature neurons, triggers hemiplegia limb spasticity after ischemic stroke by affecting neuronal excitability. Our previous study revealed that the Chinese herb Baishaoluoshi Decoction decreases hemiplegia limb spasticity in poststroke spasticity (PSS) patients. This study aimed at elucidating on the effects of Baishaoluoshi Decoction on the BDNF/TrKB-KCC2 pathway in PSS rat models. METHODS: Middle cerebral artery occlusion (MCAO) was adopted for the establishment of PSS rat models. Muscle tension was evaluated by Modified Ashworth Scale. Nissl staining and transmission electron microscopy were used to measure the protective effects of Baishaoluoshi Decoction on ischemic injury-induced neuronal damage due to MCAO. Expression levels of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were detected by immunohistochemical staining. RESULTS: It was found that Baishaoluoshi Decoction suppressed hemiplegia limb spasticity and alleviated the damage in neurons and synapses in PSS rat models. Importantly, the expression of BDNF, TrKB, and KCC2 in brain tissues around the infarct and brainstem were significantly upregulated after treatment with low-dose and high-dose Baishaoluoshi Decoction. CONCLUSION: Suppression of spasticity by Baishaoluoshi Decoction in PSS rat models may be correlated with upregulated BDNF/TrKB-KCC2 pathway, which may be a complementary therapeutic strategy for PSS.

Factors associated with relapses in relapsing-remitting multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: The relapse is character of relapsing-remitting multiple sclerosis. The therapeutic goal is to reduce the risk of relapse. Factors associated with relapses can help to manage and prevent relapses. In addition, patients and doctors all pay attention to it. However, there are differences between studies. Our aim is to summarize factors associated with relapses in relapsing-remitting multiple sclerosis (RRMS). METHODS: PubMed, EMBASE, Web of science, Cochrane library, CNKI, Wanfang, SinoMed, and VIP were searched to identify risk factors about relapses in RRMS, which should be in cohort or case-control studies. This article was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The quality of studies was evaluated by the Newcastle-Ottawa Scale (NOS). Meta-analysis, subgroup and sensitivity analyses, and publication bias were all performed with Stata. This research has been registered on the international prospective register of systematic reviews (PROSPERO, CRD42019120502). RESULTS: 43 articles were included. Infection, postpartum period, risk gene, stress, and vitamin D were risk factors for relapses in RRMS. Pregnancy period was the protective factor. Among those, infection increased the risk of relapses in infection period (relative risk [RR], 2.07 [confidence interval (CI), 1.64 to 2.60]). Women in the postpartum period increased the risk of relapses compared with women before pregnancy (RR, 1.43 [CI, 1.19 to 1.72]), or women in pregnancy period (RR, 2.07 [CI, 1.49 to 2.88]). Women in the pregnancy period decreased the risk of relapses (RR, 0.56 [CI, 0.37 to 0.84]) compared with women before pregnancy. However, fewer studies, heterogeneity, and sample size were the limitations. CONCLUSION: It is reliable to adopt results about infection, pregnancy period, and postpartum period.

Capsaicin and dihydrocapsaicin induce apoptosis in human glioma cells via ROS and Ca2+­mediated mitochondrial pathway.

Human glioma is the most common type of primary brain tumor and one of the most invasive and aggressive tumors, which, even with treatments including surgery, radiotherapy and chemotherapy, often relapses and exhibits resistance to conventional treatment methods. Developing novel strategies to control human glioma is, therefore, an important research focus. The present study investigated the mechanism of apoptosis induction in U251 human glioma cells by capsaicin (Cap) and dihydrocapsaicin (DHC), the major pungent ingredients of red chili pepper, using the Cell Counting Kit­8 assay, transmission electron microscopy analysis, flow cytometry analysis, laser scanning confocal microscope analysis and immunohistochemical staining. Treatment of U251 glioma cells with Cap and DHC resulted in a dose­ and time­dependent inhibition of cell viability and induction of apoptosis, whereas few effects were observed on the viability of L929 normal murine fibroblast cells. The apoptosis­inducing effects of Cap and DHC in U251 cells were associated with the generation of reactive oxygen species, increased Ca2+ concentrations, mitochondrial depolarization, release of cytochrome c into the cytosol and activation of caspase­9 and ­3. These effects were further confirmed by observations of the anti­tumor effects of Cap and DHC in vivo in a U251 cell murine tumor xenograft model. These results demonstrate that Cap and DHC are effective inhibitors of in vitro and in vivo survival of human glioma cells, and provide the rationale for further clinical investigation of Cap and DHC as treatments for human glioma.

[Effects of granules for nourishing kidney and strengthening brain on main symptoms of kidney-yin deficiency and blood stasis syndrome and hemorrheological characteristics of brain atrophy].

OBJECTIVE: To explore the influence of granules for nourishing kidney and strengthening brain (GNKSB) on main symptoms of kidney-yin deficiency and blood stasis syndrome and the hemorrheological characteristics of brain atrophy patients. METHODS: Ninety patients of brain atrophy with kidney-yin deficiency and blood stasis syndrome were randomly divided into two groups. Sixty cases in treatment group were treated with GNKSB, and the 30 cases in control group were treated with piracetam for 8 weeks. RESULTS: The effective rate of treatment group was 73.3%, with significant difference as compared with 46.6% of the control group (P<0.01). The scores of symptom-assessment of the two groups were also significantly different (P<0.01). The mini-mental state examination of treatment group was obviously improved, and was significantly different as compared with the control group (P<0.01). The scores of Hasegawa's dementia scale and activities of daily living were increased, but without significant difference as compared with the control group. The platelet aggregation rate was improved, with significant difference as compared with the control group (P<0.05). The whole blood viscosity was also improved obviously, but without significant difference as compared with the control group. CONCLUSION: GNKSB is effective for kidney-yin deficiency and blood stasis syndrome of brain atrophy patients and can improve their mental state and the hemorrheological indexes.